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Signaling of Cell Death in Physiology and Disease

Overview of Research in Guo Lab

Many diseases in humans are associated with dysregulation of cell death and survival. Excessive cell death, via apoptosis, necrosis, or other forms of cell death, leads to lost of functional cells and is linked to diseases in various systems related to ischemia, myocardioinfarction, stroke, neurodegenerative disorders (including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and spinal muscular atrophy), renal failure, osteoporosis, and complications associated with diabetes and HIV infection. On the other hand, aberrant repression of cell death may be causally linked to tumorigenesis (cancers), autoimmune diseases, and productive viral infection.

Current Research Interests/Areas

Current research in our laboratory centers on some of the fundamental questions in the life and death of cells in a variety of organ systems and diseases.

First, we examine how specific genetic mutations and cell death proteins regulate intracellular pathways that control neuronal life and death associated with neurodegenerative diseases. In this respect, we are specifically looking at the pathogenic mechanisms of presenilin-1 (PS-1) mutations and pro-apoptotic actions of prostate apoptosis response-4 (Par-4) protein in several transgenic mouse models of Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Mutations in presenilins-1 are responsible for majority of early onset familial AD cases, while elevated levels of Par-4 expression are associated with increased vulnerability of neurons to apoptosis.

Work in Dr. Guo's lab has contributed to our understanding of a number of mechanisms for dementia of Alzheimer's type caused by the heritable alterations of genetic information in presenilin proteins, which included the investigation of neuronal cell death process in the first mouse "knock-in" model of a naturally occurring presenilin-1 mutation responsible for an early-onset form of Alzheimer disease. We also study the mechanisms by which specific proteins regulate cholinergic neurotransmission and synaptic function.

Secondly, we have recently expanded our study to include the mechanisms by which specific cell death and/or survival proteins regulate apoptosis in models of human diseases outside the central nervous system.

Specifically, we are looking at how aberrant regulation of the apoptotic machinery is involved in pathological conditions such as acute renal failure induced by ischemia/reperfusion, diabetes, cardiovascular problems, bone disease, and cancer. One of the factors we are currently working on is apoptosis antagonizing transcription factor (AATF), a novel leucine zipper protein that interacts directly with Par-4 and functions as an endogenous antagonist of Par-4 activity in many physiological and pathological settings.

Our studies involve the application of a variety of gene transfer, targeting and expression techniques, including those in applied in vitro in cultured cells and in vivo in transgenic and/or knockin mouse models. The overall goal of our research is to understand the molecular and cellular mechanisms of cell death in human diseases, and to identify novel therapeutic strategies using genetic and/or pharmacological manipulations.